SEARCH

SEARCH BY CITATION

Keywords:

  • biomedicine;
  • cellular therapy;
  • good manufacturing practices;
  • stem cells

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. European regulation on ATMP
  5. Minimal manipulations
  6. The Committee for Advanced Therapies
  7. Conclusions
  8. Acknowledgements
  9. Disclosures
  10. References

Cell-based medicine is regulated in Europe by Regulation no. 1394/2007 of the European Parliament and of the Council. This regulation defines a new category of products named ‘advanced therapy medicinal products’ and provides rules for their marketing authorization, instructions for the definition of product characteristics, specifications on product labelling and product package leaflet. Moreover, it defines the types of cell or tissue manipulations that are not associated to the category of ‘engineered’ cells or tissues. Finally, it describes the composition and function of the Committee for Advanced Therapies, which can be consulted for the categorization of novel biomedicine products.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. European regulation on ATMP
  5. Minimal manipulations
  6. The Committee for Advanced Therapies
  7. Conclusions
  8. Acknowledgements
  9. Disclosures
  10. References

Recent discoveries providing evidence that cells can be effective therapeutic tools for tissue and organ repair have prompted the development of a novel branch of medicine called ‘biomedicine’ or ‘regenerative medicine’. Similarly to many other innovative scientific fields, an unexpected expansion of knowledge has prompted the development of specific guidelines, norms and rules to properly manage issues such as patient protection, freedom of research, intellectual property and use of resources. Rather than developing an entirely novel set of laws and regulations, the European Commission has chosen to adapt the consolidated set of rules governing the pharmaceutical sector – mostly applied to the production of chemical drugs – to the manufacture of cellular products. This process has been expanded to include gene therapy, somatic cell therapy and tissue engineering, which form the current regulatory category of ‘advanced therapy medicinal products’ (ATMP) (Table 1).

Table 1.   Therapeutic fields covered by Regulation no. 1394/2007
Gene therapy
Somatic cell therapy
Tissue engineering

The aim of this article is to review the European regulation of cell-based medicine from the perspective of an academic institution mainly interested in the preparation and use of ATMP for experimental purposes.

European regulation on ATMP

  1. Top of page
  2. Abstract
  3. Introduction
  4. European regulation on ATMP
  5. Minimal manipulations
  6. The Committee for Advanced Therapies
  7. Conclusions
  8. Acknowledgements
  9. Disclosures
  10. References

A detailed description of ATMP regulation is available at the European Medicines Agency (EMA) website [1].

Regulation (EC) no. 1394/2007 provides specific rules concerning the authorization, supervision and pharmacovigilance of ATMP. It was published on 10 December 2007 in the Official Journal of the European Union and amends Directive 2001/83/EC and Regulation (EC) no. 726/2004. This Regulation is a lex specialis, which introduces additional provisions to those laid down in Directive 2001/83/EC. The scope of this Regulation should be to regulate advanced therapy medicinal products which are intended to be placed on the market by Member States and either prepared industrially or manufactured by a method involving an industrial process, in accordance with the general scope of the Community pharmaceutical legislation laid down in Title II of Directive 2001/83/EC. Advanced therapy medicinal products which are prepared on a non-routine basis according to specific quality standards, and used within the same Member State in a hospital under the exclusive professional responsibility of a medical practitioner, to comply with an individual medical prescription for a custom-made product for an individual patient, should be excluded from the scope of this Regulation whilst at the same time ensuring that relevant Community rules related to quality and safety are not undermined’.

Another important specification of Regulation no. 1394/2007 regards combinations of biological medicinal products and medical devices, as it clearly states that ‘whatever the role of the medical device, the pharmacological, immunological or metabolic action of these cells or tissues should be considered to be the principal mode of action of the combination product. Such combination products should always be regulated under this Regulation’.

The above provisions clearly set a boundary between typical, large industrial ATMP production processes and international marketing programs and a small-scale, non-routine ATMP preparation for an individual patient in a hospital, under the exclusive responsibility of a physician, with the specification that the latter ‘should’ not be managed by Regulation no. 1394/2007 (Table 2). This exclusion may falsely generate an impression of a ‘more permissive’ framework for ATMP production in hospitals. Nonetheless, as can in fact be logically expected, Regulation no. 1394/2007 prescribes full compliance with ‘specific quality standards’ and ‘Community rules related to quality and safety’ also for in hospital non-routine preparations for individual patients.

Table 2.   Conditions of ATMP preparation and use excluded from the scope of Regulation no. 1394/2007
  1. ATMP, advanced therapy medicinal products.

‘Homologous’ use
Non-routine basis
Non-exportation
In hospital use
Use under exclusive professional responsibility of a medical practitioner
Individual medical prescription
Custom-made product for individual patient

Besides the large set of mandatory rules for industry contained in Regulation no. 1394/2007, this prescription is highly relevant for academic institutions, as it translates into the practical consequence of limiting ATMP preparation in very expensive infrastructures – frequently called ‘Cell Factories’– fully compliant with the Good Manufacturing Practice (GMP) norms that regulate the pharmaceutical industry and certified for GMP by the competent regulatory authority, by dedicated staff trained and qualified for compliance with those norms [2]. This can significantly increase the operational costs of advanced therapies if organizational efforts are not developed to share ATMP preparation in a networked setting linking several hospitals and serving a large geographical area. A fully operative network of three Cell Factories able to provide ATMP to many academic institutions across national borders – named Production Assistance for Cellular Therapies (PACT) – has been implemented in the United States [3].

Regulation no. 1394/2007 contains also important provisions to facilitate the development and use of ATMP in hospitals. As stated in article 19, ‘By way of derogation from Regulation (EC) no. 297/95, the fee for marketing authorization shall be reduced by 50% if the applicant is a hospital or a small or medium-sized enterprise and can prove that there is a particular public health interest in the Community in the advanced therapy medicinal product concerned’.

Another important regulatory document relevant to ATMP is Directive 2004/23/EC of the European Parliament and of the Council, which sets standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells.

Both Directive 2004/23/EC and Regulation no. 1394/2007 are based on the respect of the anonymity of both donor and recipient, altruism of the donor and solidarity between donor and recipient. Accordingly, Regulation no. 1394/2007 states that ‘As a matter of principle, human cells or tissues contained in advanced therapy medicinal products should be procured from voluntary and unpaid donation. Member States should be urged to take all necessary steps to encourage a strong public and non-profit sector involvement in the procurement of human cells or tissues, as voluntary and unpaid cell and tissue donations may contribute to high safety standards for cells and tissues and therefore to the protection of human health’.

Minimal manipulations

  1. Top of page
  2. Abstract
  3. Introduction
  4. European regulation on ATMP
  5. Minimal manipulations
  6. The Committee for Advanced Therapies
  7. Conclusions
  8. Acknowledgements
  9. Disclosures
  10. References

The concept of minimal manipulation evolved from the first definition of ‘manipulations that do not affect cell proliferation or do not lead to changes in genotype’ [4] to the more recent simplification contained in Regulation no. 1394/2007 that defines cells or tissues as substantially manipulated or ‘engineered’ when they undergo a process aimed at achieving biological characteristics, physiological functions or structural properties relevant for the intended regeneration, repair or replacement. Manipulations such as cutting, grinding, shaping, centrifugation, soaking in antibiotic or antimicrobial solutions, sterilization, irradiation, cell separation, concentration or purification, filtering, lyophilization, freezing, cryopreservation, or vitrification are not considered ‘substantial manipulation’. However, cells or tissues that undergo such processes but are not intended to be used for the same functions in the recipient as in the donor – a condition defined as ‘non-homologous use’– are included in substantially manipulated or ‘engineered’ cell product. The current definition of ‘non-substantially manipulated cell products’ that excludes the non-homologous use from this category is based on a precautionary approach aimed at protecting human subjects involved in clinical experimentations from unexpected effects because of interaction of the cells with a different microenvironment.

The Committee for Advanced Therapies

  1. Top of page
  2. Abstract
  3. Introduction
  4. European regulation on ATMP
  5. Minimal manipulations
  6. The Committee for Advanced Therapies
  7. Conclusions
  8. Acknowledgements
  9. Disclosures
  10. References

Regulation no. 1394/2007 recognizes that ‘the evaluation of advanced therapy medicinal products often requires very specific expertise, which goes beyond the traditional pharmaceutical field and covers areas bordering on other sectors such as biotechnology and medical devices’. For this reason, a Committee for Advanced Therapy was formed, which is responsible for preparing a draft opinion on the quality, safety and efficacy of ATMP, to be approved by the EMA’s Committee for Medicinal Products for Human Use. The Committee for Advanced Therapies can be consulted for categorization of biological medicinal products among ATMP.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. European regulation on ATMP
  5. Minimal manipulations
  6. The Committee for Advanced Therapies
  7. Conclusions
  8. Acknowledgements
  9. Disclosures
  10. References

The nascent field of biomedicine has been the object of extensive regulation in the last few years, both in Europe and in other continents. Similarly to other sets of norms governing the production and use of medicinal products containing cells or tissues, the main purpose of the European regulation is to safeguard public health. Scientists and regulatory agencies should cooperate to harmonize regulations at the international level, as this would facilitate the development of clinical trials with sufficient statistical power to answer a number of pending questions on the efficacy and safety of ATMP.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. European regulation on ATMP
  5. Minimal manipulations
  6. The Committee for Advanced Therapies
  7. Conclusions
  8. Acknowledgements
  9. Disclosures
  10. References

Grants from Fondazione Il Sangue, Milan; Centro Nazionale Sangue, Rome; Ministry of Health, Rome; Regione Lombardia, Milan; IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan; 7th FP European Commission CASCADE (Cultivated Adult Stem Cells as Alternative for Damaged tissuE), no. 223236; HEALTH-F5-2009-223236; 7th FP European Commission REBORNE (Regenerating Bone defects using new Biomedical Engineering Approaches) no. 241879, HEALTH-F5-2009-241879, Foundation NovusSanguis and Foundation Jerom Lejeune.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. European regulation on ATMP
  5. Minimal manipulations
  6. The Committee for Advanced Therapies
  7. Conclusions
  8. Acknowledgements
  9. Disclosures
  10. References